I. Field of the Invention
The present invention relates generally to the fields of biology and medicine. More particularly, it concerns compositions and methods for promoting bone and cartilage growth and repair.
II. Description of Related Art
The development of a functional tissue such as bone requires the concerted action of a number of microenvironmental signals: cytokines/growth factors, extracellular matrix (ECM) molecules, and cell:cell interactions. Moreover, these regulatory signals must be queued in the appropriate temporal and spatial order, resulting in a developmental microenvironment that facilitates three-dimensional growth. The skeletal system is no exception to such requirements. It is well understood that a number of cytokines/growth factors, such as TGF-β1 family members, modulate bone formation, and that ECM molecules like osteonectin, osteocalcin, and Type I and II collagen, etc., are important in both osteogenesis and chondrogenesis.
Current methods for the repair of bone defects include grafts of organic and synthetic construction. Three types of organic grafts are commonly used: autografts, allografts, and xenografts. An autograft is tissue transplanted from one site to another in the patient, and thus benefits from the absence of an immune response. However, using an autograft requires a second surgical site, increasing the risk of infection. Further, bone for grafting comes from a limited number of sites, e.g., the fibula, ribs and iliac crest. An allograft is tissue taken from a different organism of the same species, and a xenograft from an organism of a different species. These tissues are readily available in larger quantities than autografts, but genetic differences between the donor and recipient may lead to rejection of the graft. All have advantages and disadvantages, yet none provides an ideal replacement for missing bone. Thus, there exists a need for improved to repair and/or replace bone in subjects suffering from bone disease or trauma.
Articular cartilage is also recalcitrant to regeneration. Articular cartilage has discrete zone of cells including superficial zone, middle zone, and deep zone. The superficial zone chondrocytes secrete superficial protein (SZP) which is encoded by the gene PRG4, homologous to lubricin, and functions as a lubricant in articular joints. In contrast, the chondrocytes in the middle or deep zones of cartilage exhibit little capacity for SZP synthesis. Moreover, camptodactyl-arthropathy-coxa-vara-pericarditis syndrome (CACP) is known to be caused by mutations in the PRG4 gene which encodes SZP. Understanding of the regulators of SZP synthesis is important for investigating disease, homeostasis of articular joint, and tissue engineering of functional superficial zone articular cartilage. Transforming growth factor-β (TGF-β) is known to possess a capacity to up-regulate SZP synthesis in articular chondrocytes (Palcy et al., 1999). Methods are needed to module TGF-β/Smad signaling in articular chondrocytes in order to provide improved treatments for the repair and/or regeneration of articular cartilage.